Chapter 12: Alcohols and Phenols

Hello

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Chapter 12: Alcohols and Phenols
Topics:
I. Structure and Properties of Alcohols
II. Acidity of Alcohols and Phenols
III. Preparation of Alcohols via Substitution or Addition
IV. Preparation of Alcohols via Reductions
V. Hello
Preparation of Diols
VI. Preparation of Alcohols via Grignard Reagents
VII. Protection of Alcohols
VIII. Preparation of Phenols NOT on tests or quizzes
IX. Reactions of Alcohols: Substitution and Elimination
X. Reactions of Alcohols: Oxidation
XI. Biological Redox Reactions (Electron Transport Chain) NOT
on tests or quizzes
XII. Oxidation of Phenol NOT on tests or quizzes
XIII. Synthesis Strategies 2 2
I. Structure and Properties of Alcohols

• Alcohols  possess  a  hydroxyl  group  (-­‐OH)  

Hello
• Hydroxyl  groups  are  extremely  common  in  natural  compounds

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I. Structure and Properties of Alcohols

Hydroxyl groups in natural compounds

Hello

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I. Structure and Properties of Alcohols

Phenols  possess  a  hydroxyl group directly attached to a

benzene ring

Hello

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I. Structure and Properties of Alcohols

• Alcohols  are  named  using  the  same  procedure  we  used  in  Chapter  4  
to  name  alkanes  with  minor  modifications  
1. Identify  the  parent  chain,  which  should  include  the  carbon  that  
the  –OH  is  attached  to  
2. Identify  and  Name   Hellothe  substituents  
3. Assign  a  locant  (and  prefix  if  necessary)  to  each  substituent.  
Give  the  carbon  that  the  –OH  is  attached  to  the  lowest  number  
possible  
4. List  the  numbered  substituents  before  the  parent  name  in  
alphabetical  order.  Ignore  prefixes  (except  iso)  when  ordering  
alphabetically  
5. The  –OH  locant  is  placed  either  just  before    
  the  parent  name  or  just  before  the  -­‐ol  suffix

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I. Structure and Properties of Alcohols

• Alcohols  are  named  using  the  same  procedure  we  used  in  Chapter  
4  to  name  alkanes  with  minor  modifications  
1. Identify  the  parent  chain

Hello

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I. Structure and Properties of Alcohols

• Alcohols  are  named  using  the  same  procedure  we  used  in  Chapter  
4  to  name  alkanes  with  minor  modifications  
3. Assign  a  locant  (and  prefix  if  necessary)  to  each  substituent.  
Give  the  carbon  that  the  –OH  is  attached  to  the  lowest  
number Hello

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I. Structure and Properties of Alcohols

• Alcohols  are  named  using  the  same  procedure  we  used  in  Chapter  
4  to  name  alkanes  with  minor  modifications  
5. The  –OH  locant  is  placed  either  just  before  the  parent  name  
or  just  before  the  -­‐ol  suffix
Hello

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I. Structure and Properties of Alcohols

• For  cyclic  alcohols,  the  –OH  group  is  always  carbon  1  

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• Common  names  for  some  alcohols  are  also  frequently  used

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I. Structure and Properties of Alcohols

Like halides, alcohols are often classified by the

type of carbon they are attached to

Hello

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I. Structure and Properties of Alcohols

• When  an  –OH  group  is  attached  to  a  benzene  ring,  the  parent  
name  is  phenol

Hello

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I. Structure and Properties of Alcohols

• Methanol  (CH3OH)  is  the  simplest  alcohol  

• With  a  suitable  catalyst,  about  2  billion  gallons  of  methanol  is  

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made  industrially  from  CO2  and  H2  every  year  

• Methanol  is  poisonous,  but  it  has  many  uses  

1. Solvent    
2. Precursor  for  chemical  syntheses    
3. Fuel

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I. Structure and Properties of Alcohols

• Ethanol  (CH3CH2OH),  produced  by  fermentation  of  grains  or  fruits  

• Industrially,  ethanol  is  made  via  acid-­‐catalyzed  hydration  of  

ethylene    (5  billion  gallons/year  in  the  U.S.  alone)  
Hello

• Ethanol  has  many  uses  

1. Solvent,  precursor  for  chemical  syntheses,  fuel.    Is  denatured  
to  avoid  heavy  taxes  
2. Human  consumption  –  ethanol  suitable  for  drinking,  and  is  
heavily  taxed.  

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I. Structure and Properties of Alcohols

• Isopropanol  CH3CH(OH)CH3,  a.k.a.  rubbing  alcohol.  

• Isopropanol  is  made  industrially  from  the  acid-­‐catalyzed  hydration  

of  propylene  
Hello

• Isopropanol  is  poisonous,  but  it  has  many  uses  

1. Industrial  solvent  
2. Antiseptic  
3. Gasoline  additive

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I. Structure and Properties of Alcohols

• The  –OH  of  an  alcohol  has  a  big  effect  on  its  physical  properties  
• Compare  the  boiling  points  below  

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• Alcohols  have  much  higher  BP’s  due  to  H-­‐bonding

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I. Structure and Properties of Alcohols

• Alcohols  with  3  carbons  or  less  are  miscible  in  water  

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• Alcohols  with  large  carbon  chains  do  not  readily  mix  with  water

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I. Structure and Properties of Alcohols

• An  alcohol’s  potency  as  an  anti-­‐bacterial  agent  depends  on  the  

size  of  the  hydrophobic  group

• The  alcohol  needs  some  

water  solubility  to  Hello
travel  
through  aqueous  media  

• To  kill  a  bacterium,  the  

alcohol  should  have  a  
significant  hydrophobic  
region  to  penetrate  
microbial  membranes

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I. Structure and Properties of Alcohols

• Hexylresorcinol  is  used  as  an  antibacterial  and  as  an  antifungal  
agent  

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• It  has  a  good  combination  of  hydrophobic  and  hydrophilic  regions

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 I. Structure and Properties of Alcohols
Provide  a  IUPAC  name  for  each  of  the  following  alcohols.

a. OH b.
OH
Br Br
Hello
OH
OH
c. d.

Cl Cl
e.

OH

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I. Structure and Properties of Alcohols
Answers:
1
5 1
a. 6 5 4 3 2 b. 3 2
OH OH
4
Br Br
5,5-dibromo-2-methyl-2-hexanol (2S,3R)-2,3,4-trimethyl-1-penanol
OH Hello
1 OH
2
c. 6 3 1
d.
2
4 6
5 3 5

4
2,6-diethylphenol (S)-2,2,4,4-tetramethylcylohexanol

8 9
Cl Cl 7

e. 1 3 5
2 4 6

OH
(3R,6R)-4,4-dichloro-6-ethyl-3-nonanol

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 II. Acidity of Alcohols and Phenols

• A  strong  base  is  necessary  to  deprotonate  an  alcohol.    NaH  is  often  
used  to  generate  the  corresponding  alkoxide:  

Hello

• Na,  K,  or  Li  metal  is  often  used  as  well:

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II. Acidity of Alcohols and Phenols

• Alkoxide  –  conjugate  base  of  an  alcohol  

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• Remember  ARIO…  to  rationalize  the  relative  acidity  of  an  alcohol

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II. Acidity of Alcohols and Phenols

• Recall  the  factors  that  affect  the  acidity  of  alcohols  and  phenols  

1. Resonance  –  phenol  is  millions  of    

  times  more  acidic  because  the    
Hello
  conjugate  base,  phenoxide,  
  is  resonance  stabilized

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II. Acidity of Alcohols and Phenols

• Recall  the  factors  that  affect  the  acidity  of  alcohols  and  phenols  

2. Induction  –  presence  of  electron  withdrawing  groups  

increases  the  acidity  of  an  alcohol  or  phenol
Hello

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II. Acidity of Alcohols and Phenols

• Recall  the  factors  that  affect  the  acidity  of  alcohols  and  phenols  

3. Solvation  Effects  –  The  more  poorly  solvated  a  conjugate  base,  

the  less  stable  it  is,  and  the  less  acidic  it’s  conjugate  acid
Hello

The  conjugate  base  of

tert-­‐butanol  is  less  stable
due  to  solvation  effects

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II. Acidity of Alcohols and Phenols

• The  tert-­‐butoxide  ion  is  sterically  hindered,  and  not  well  solvated

Hello

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 II. Acidity of Alcohols and Phenols
Draw  the  structure  of  the  alkoxide  ion  that  is  formed  from  each  of  
the  following  reactions.
OH
Na
a.

Hello
OH
NaH
b.

OH
Li
c.

OH
NaH
d.

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 II. Acidity of Alcohols and Phenols
Answers:
OH O Na
Na
a.

Hello
OH
NaH O Na
b.

OH O Li
Li
c.

OH O Na
NaH
d.

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 II. Acidity of Alcohols and Phenols
Identify  the  most  acidic  proton  in  each  of  the  following  molecules.

Cl
OH
HO Cl OH

a. HO b.

Cl
Hello
Cl

O
OH

c. d.

HO
HO OH

OH O OH O

e.

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II. Acidity of Alcohols and Phenols
Answers:
Primary is more acidic than tertiary Equal number of resonance structures however,
It is less hindered so it can be stabilized there are more electron withdrawing chlorines
by more solvent molecules. near this OH.
Cl
OH
HO Cl OH

a. HO b.
Hello
Cl

Cl
More resonance structures
do to the nearby C=O and the
O C=O is electron withdrawing
OH

c. d.

HO
HO OH
More acidic due to more possible
More acidic due to the presence of more resonance structures resonance structures
and the C=O is electron withdrawing

OH O OH O

e.

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III. Preparation of Alcohols via Substitution or Addition

• Alcohols  can  be  synthesized  from  alkyl  halides  via  substitution:  

Hello
• The  substitution  occurs  by  SN1  or  SN2,  depending  on  the  substrate:

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III. Preparation of Alcohols via Substitution or Addition

• Alcohols  can  by  synthesized  from  alkenes  via  addition  reactions:  

Hello

• Recall  that  acid-­‐catalyzed  hydration  yield  Markovnikov  addition  

• Hydroboration-­‐oxidation  yields  anti  Markovnikov  addition

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III. Preparation of Alcohols via Substitution or Addition
Lets  review  what  you  have  already  learned  from  previous  chapters.    
Identify  the  reagents  that  you  would  use  to  accomplish  the  
following  transformations.
HO
Br

OH
d.
a.
Hello

OH

b. Br OH e.

OH f.
c. HO

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III. Preparation of Alcohols via Substitution or Addition
Answers:

HO Br HO
Br

1. t-BuOK 2. H3O+
a. 1. t-BuOK
2. H3O+

Hello Hoffman Product

or
HO
Br

H 2O
heat

SN1 reaction using water as the weak nucleophile

though E1 may be an undesired byproduct.

Br NaOH OH Since this a primary alkyl halide, SN2 will dominate

b. over E2. A 2 step approach using a strong non-nucleophilic
base followed by hydroboration will also work

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III. Preparation of Alcohols via Substitution or Addition
Answers:

Br NaOH OH Since this a primary alkyl halide, SN2 will dominate

b. over E2. A 2 step approach using a strong non-nucleophilic
base followed by hydroboration will also work

H2O,H2SO4 Initial protonation of the double bond will leave the positive
OH
c. charge on the most substituted tertiary position which is
Hello subsequently attacked by a molecule of water.

1. BH3·THF Hydroboration always puts the OH on the least substituted

d. OH position. Anti-Markovnikov selectivity.
2. H2O2, NaOH

OH
You do NOT want to use sulfuric acid and water here. You
will get carbocation rearrangements. Therefore you need to
1. Hg(OAc)2, H2O use oxymercuration to avoid methyl shifts.
e. 2. NaBH4

1. BH3·THF Hydroboration always puts the OH on the least substituted

f. position. Anti-Markovnikov selectivity.
2. H2O2, NaOH
HO

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III. Preparation of Alcohols via Substitution or Addition

Identify  the  reagents  that  you  would  use  to  accomplish  the  following  
transformations.

a. 1-hexeneHello ⟶ a primary alcohol

b. 3,3-dimethyl-1-hexene ⟶ a secondary alcohol
c. 2-methyl-1-hexene ⟶ a tertiary alcohol

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III. Preparation of Alcohols via Substitution or Addition
Answers:

1. BH3·THF HO Hydroboration always puts the OH on the

a. least substituted position. Anti-Markovnikov.
2. H2O2, NaOH
1-hexene a primary alcohol

Hello OH
1. Hg(OAc)2, H2O You do NOT want to use sulfuric acid and water here. You
b. 2. NaBH4 will get carbocation rearrangements. Therefore you need to
use oxymercuration to avoid methyl shifts.
3,3-dimethyl-1-hexene a secondary alcohol

H2O,H2SO4 HO
c. Initial protonation of the double bond will leave the positive
charge on the most substituted tertiary position which is
subsequently attacked by a molecule of water.
2-methyl-1-hexene a tertiary alcohol

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IV. Preparation of Alcohols via Reducitons

• A  third  method  to  prepare  alcohols  is  by  the  reduction  

of  a  carbonyl.  What  is  a  carbonyl?  
• Reductions  involve  a  change  in  oxidation  state  
• Oxidation  state   Hello
are  a  method  of  electron  bookkeeping  
• Recall  how  we  used  formal  charge  as  a  method  of  
electron  bookkeeping    
– Each  atom  is  assigned  half  of  the  electrons  it  is  sharing  with  
another  atom  
– What  is  the  formal  charge  on  carbon  in  methanol?

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IV. Preparation of Alcohols via Reducitons

• To  determine  the  oxidation  state  of  an  atom,  imagine  the  electrons  
in  a  bond  as  a  lone  pair  on  the  more  electronegative  atom

Hello

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IV. Preparation of Alcohols via Reducitons
• Oxidation  states  for  carbon  ranges  from  −4  to  +4  

Hello

• Oxidation  Reaction  –  carbon’s  oxidation  state  is  increased  

• Reduction  Reaction  –  carbon’s  oxidation  state  is  decreased
My method: Look at the connections to the central carbon and add up all
plus’s and minuses described below:
1. If the connection is to another carbon, ignore it.
2. If the connection is to an H or B, add a minus.
- Add a minus if the element is less electronegative than C.
3. If the connections is anything besides an H,B, or C add a plus.
- Add a plus if the element more electronegative than C. 41
IV. Preparation of Alcohols via Reducitons
• Converting  a  carbonyl  to  an  alcohol  requires  a  reducing  agent  

Hello
• The  reducing  agent  is  then  oxidized  in  the  process,  while  the  
substrate  (carbonyl  is  reduced)  

• The  reduction  of  the  carbonyl  group,  overall,  results  in  the  addition  
of  H  and  H  across  the  π  bond  
• Remember  OIL  RIG        Oxidation  Is  Losing      Reduction  Is  Gaining

• What  is  the  oxidation  state  of  the  central  carbon  in  each  molecule  
above?    Did  this  central  carbon  gain  or  lose  electrons? 42
IV. Preparation of Alcohols via Reducitons

• Converting  a  carbonyl  to  an  alcohol  requires  a  reducing  agent  

Hello

• The  reducing  agent  is  then  oxidized  in  the  process,  while  the  
substrate  (carbonyl  is  reduced)  

• The  reduction  of  the  carbonyl  group,  overall,  results  in  the  addition  
of  H  and  H  across  the  π  bond

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used:  

1. Catalytic  Hydrogenation:    

Hello

This  method  is  rarely  used;  high  temp  and  pressure  is  required

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used:  

2. Sodium  Borohydride  (NaBH4)  –  common  reducing  agent  for  

aldehydes  and  ketones
Hello

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used  

• NaBH4  is  a  soluble  source  of  hydride  (H−)  which  does  nucleophilic  
addition  to  the  carbonyl  carbon,  followed  by  proton  transfer  from  
the  solvent:
Hello

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used  

• When  an  unsymmetrical  ketone  is  reduced,  a  new  chiral  center  is  
created  and  a  pair  of  stereoisomers  is  obtained

Hello

Unsymmetrical  ketone  
has  two  different  R  groups

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used:  

3. Lithium  Aluminum  Hydride  (LiAlH4)  –  another  common  

reducing  agent  for  reducing  carbonyl  compounds  
Hello

Lithium  Aluminum  Hydride  is  often  abbreviated  as  LAH

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used  

• LiAlH4  and  NaBH4  are  structurally  similar  hydride  reagents  

Hello

• But,  LAH  is  way  more  reactive  than  NaBH4

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IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used  

• LiAlH4  is  much  more  reactive  and  cannot  be  used  in  presence  of  a  
protic  solvent.    The  proton  source  (H2O)  has  to  be  added  after  
carbonyl  is  reduced.
Hello

50
IV. Preparation of Alcohols via Reducitons

• There  are  three  reducing  agents  that  can  be  used  

• LiAlH4  is  much  more  reactive  and  cannot  be  used  in  presence  of  a  
protic  solvent.    The  proton  source  (H2O)  has  to  be  added  after  
carbonyl  is  reduced.
Hello

51
IV. Preparation of Alcohols via Reducitons
Predict the Products

Hello
H2 1. NaBH4
Pt 2. H2O

1. LAH
2. H2O

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IV. Preparation of Alcohols via Reducitons

• Hydride  delivery  agents  are  selective  for  the  carbonyl  group,  

whereas  hydrogenation  is  not.  

Hello

• Catalytic  hydrogenation  reduces  the  carbonyl  AND  the  alkene

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IV. Preparation of Alcohols via Reducitons

• The  reactivity  of  hydride  delivery  agents  can  be  fine-­‐tuned  by  using  
derivatives  with  varying  R-­‐groups    

Hello

– Alkoxides  
– Cyano  
– Sterically  hindered  groups

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IV. Preparation of Alcohols via Reducitons

• LAH  is  strong  enough  to  also  reduce  esters  and  carboxylic  acids,  
whereas  NaBH4  is  generally  not  

Hello

• Reduction  of  carboxylic  acids  &  esters  yield  primary  alcohols

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IV. Preparation of Alcohols via Reducitons
Comparing LAH to NaBH4

Hello

• Ketones and aldehydes are more reactive than carboxylic acids and
esters since there is less resonance stabilization.

• Lithium aluminum hydride is more reactive than NaBH4 since the Al-H
bond is weaker than the B-H bond. 56
IV. Preparation of Alcohols via Reducitons

• Reduction  of  an  ester  requires  2  equivalents  of  hydride  

• The  first  two  steps  result  in  formation  of  an  aldehyde,  which  is  then  
reduced  to  alcohol  as  previously  discussed.  

Hello

• Methoxide  is  not  a  good  leaving  group,  but  acts  like  one  here  
because  the  high  energy  intermediate  becomes  a  stable  aldehyde
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 IV. Preparation of Alcohols via Reducitons
Identify  whether  the  following  compounds  have  been  oxidized,  
reduced,  or  neither.    First  to  do  this  without  performing  any  
calculations.    Next,  check  your  answers  by  calculating  oxidation  states.

O O
a.
O
Hello
Cl Cl
d.
Cl OH

OH O
O O
b. e.
H OH

O O
O
c. OH f. O

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 IV. Preparation of Alcohols via Reducitons
Answers:    OIL  RIG      Oxidation  Is  Losing,  Reduction  Is  Gaining
O Cl Cl O O
a.
No d.
No
Change Cl
Change OH
+2 +2 +3 +3
Each bond of the central carbon to oxygen or
Each bond to oxygen adds a + 1
chlorine which is more electronegative adds a
Each bond to chlorine adds a +1
+1 oxidation state (1 + 1 = +2).
Each bond to carbon has no effect
Two bonds of the central carbon to carbon
atoms have no effect since they are the same
element. Hello OH O
O O
Oxidized Oxidized
b. e.
+0 +2
+1 H +3 OH One hydrogen here!
Each bond to oxygen adds a + 1
Each bond to hydrogen adds a −1 since H is less Each bond to oxygen adds a + 1
electronegative than carbon Each bond to hydrogen adds a −1.
Each bond to carbon has no effect Each bond to carbon has no effect

O O
O Reduced Oxidized
c. f.
+1 OH
+2 +3 O

+2
Each bond to oxygen adds a + 1 Each bond to oxygen adds a + 1
Each bond to carbon has no effect Each bond to carbon has no effect
59
 IV. Preparation of Alcohols via Reducitons
Predict  the  major  product  for  each  reaction  AND  write  out  the  
complete  mechanism  for  the  reaction

O O
1. LiAlH4 NaBH4
a.
H
Hello
2. H O
2
c.
MeOH

O
O 1. LiAlH4 1. xs LiAlH4
b. d.
2. H2O 2. H2O
O

60
 IV. Preparation of Alcohols via Reducitons
Answers:

O OH
1. LiAlH4 O 1. LiAlH4
a. b. OH
H
2. H2O
Hello H 2. H2O

H racemic H
H racemic
H Al H H Al H
O H H
H H O H
O Li

O
Li
H

racemic racemic

61
 IV. Preparation of Alcohols via Reducitons
Answers:
OH
O
O OH
NaBH4 1. xs LiAlH4
c. d.
MeOH 2. H2O
Racemic
O
H O H
H
H B H
H Al H
H
Hello
O Na
H H
O H

O
Racemic

Li O

O
O
Racemic
H

H Al H

62
V. Preparation of Diols

• Diols  are  named  using  the  same  method  as  alcohols,  except  the  “e”  
is  not  dropped  from  the  alkane  name,  and  the  suffix  “diol”  is  used.  

Hello

• The  term  glycol  is  also  used  to  describe    

  a  compound  with  two  hydroxyl  groups

63
V. Preparation of Diols

Diols  can  be  prepared  from  the  reduction of diketones

Hello

64
V. Preparation of Diols

Recall the methods we discussed in chapter 9 to

convert an alkene into a diol

conditions?
Hello

conditions?

65
V. Preparation of Diols

Recall the methods we discussed in chapter 9 to

convert an alkene into a diol

Hello

66
 V. Preparation of Diols
Determine  the  structure  for  unknown  compounds  A  &  B  and  
determine  conditions  A  -­‐  E.    Also  condition  D  ≠  condition  E
Condition A
Unknown B
OH OH

Hello
1. O3
2. DMS
OH
Condition B

OH

Unknown A O O
Condition C

+ Enantiomer

HO OH
Condition D

HO OH

Condition E

67
V. Preparation of Diols H2, Pd or Answers:
NaBH4, MeOH or

Unknown B O 1. LiAlH4
2. H2O

O Condition A
OH OH
H

1. O3
2. DMS
Condition B OH
H2, Pd
Unknown A

OH
O O Condition C
O O
cat. OsO4, NMO
+ Enantiomer

HO OH

NaBH4, MeOH
Condition D

HO OH
Condition E

1. LiAlH4
2. H2O

68 68
VI. Preparation of Alcohols via Grignard Reagents

• Grignard  reagents  are  often  used  in  the  synthesis  of  alcohols  
• To  form  a  Grignard,  an  alkyl  halide  is  treated  with  Mg  metal

Hello

69
VI. Preparation of Alcohols via Grignard Reagents

• The  electronegativity  difference  between  C  (2.5)  and  Mg  (1.3)  is  

great  enough  that  the  bond  has  significant  ionic  character  

Hello

• The  carbon  atom  behaves  like  a  carbon  anion,  and  is  a  strong  
nucleophile,  as  well  as  a  strong  base

70
VI. Preparation of Alcohols via Grignard Reagents

• Grignard  reagents  react  like  LAH,  and  will  attack  the  carbonyl  group  
of  a  ketone  or  an  aldehyde  

Hello

★  The  key  difference  –  Grignard  reaction  give  a  new  C-­‐C  bond!

71
VI. Preparation of Alcohols via Grignard Reagents

• Because  the  Grignard  is  both  a  strong  base  and  a  strong  

nucleophile,  care  must  be  taken  to  protect  it  from  exposure  to  
water  or  alcohols  

Hello

• Anhydrous  ethers  are  usually  used  as  solvents  for  Grignard  

reactions

72
VI. Preparation of Alcohols via Grignard Reagents

Grignard examples

Hello

73
 VI. Preparation of Alcohols via Grignard Reagents
Identify  all  the  possible  methods  that  can  be  used  to  synthesize  the  
following  compound  using  the  Grignard  reaction.    

OH
Hello

74
VI. Preparation of Alcohols via Grignard Reagents
Answers:
O OH

1. MeMgBr
2. H2O

O Hello OH

1. EtMgBr
2. H2O

OH
O
1. PhMgBr
2. H2O

75
 VI. Preparation of Alcohols via Grignard Reagents
Show  how  a  Grignard  addition  reaction  can  be  used  to  prepare  each  
of  the  following  compounds  below.  

OH OH
a. c. e.
Hello OH

OH OH OH
b. d. f.

Two  of  these  compounds  can  be  prepared  from  and  ester.    Identify  
these  two  compounds  and  explain  why  the  other  compounds  cannot  
be  prepared  from  an  ester.
76
VI. Preparation of Alcohols via Grignard Reagents
Answers:
O
1. PrMgBr O
1. PrMgBr
2. H2O OH b.
a. H 2. H2O
H

O
O OH
1. MeBr
1. MeBr
2. H2O
H
Hello H
2. H2O
This product has two identical R
groups so it can be synthesized
O
from an ester
1. xs. MeBr
2. H2O
OR
c. O 1. PrMgBr OH
2. H2O d.
H H

O 1. EtMgBr

H 2. H2O
OH

O
1. BnMgBr
Benzyl (Bn) group 2. H2O
H

77
VI. Preparation of Alcohols via Grignard Reagents
Answers:

1. BuMgBr O
O f. 1. BnMgBr
e.
2. H2O 2. H2O

Hello OH

O 1. EtMgBr O
1. MeMgBr
2. H2O OH 2. H2O
Bn Bn

O O This product has two identical R

1. MeMgBr 1. xs BnMgBr groups so it can be synthesized
from an ester
2. H2O 2. H2O
OR

78
 VI. Preparation of Alcohols via Grignard Reagents
During  the  synthesis  of  (+)-­‐carissone,  a  Grignard  reaction  was  used  to  
convert  compound  1  into  compound  2.    

Grignard
Addition Oxidation

HO CO2Me HO O
Hello OH OH
1 2 (+)-Carissone

Identify  the  Grignard  reagent  that  is  needed  for  the  transformation  of  
compound  1  into  compound  2.  
Typically,  two  equivalents  of  Grignard  reagent  are  necessary  to  completely  
reduce  an  ester  to  the  alcohol.    Why  is  three  equivalents  required  in  this  case.  
Draw  a  complete  mechanism  for  the  conversion  of  compound  1  into  
compound  2.    Make  sure  you  use  all  three  equivalents  of  Grignard  reagent  in  
your  mechanism. 79
 VI. Preparation of Alcohols via Grignard Reagents
Answers:    Methyl  magnesium  bromide  is  the  Grignard  reagent  required  
and  three  equivalents  are  required  because  the  first  equivalent  
deprotonates  the  alcohol.    

Me MgBr

H
Hello O
O O
O

O CO2Me
OMe
Me OMe

MgBr

O
H H
quench
OH with H2O O
O O
HO O
Me
H
MgBr
O H

80
VII. Protection of Alcohols

• Consider  the  reaction  below.    

Hello

• The  alcohol  can  act  as  an  acid,  so  a  Grignard  reagents  and  alcohols  
are  incompatible  
• The  Grignard  would  deprotonate  the  alcohol  forming  an  
alkoxide  
• The  alcohol  can  be  protected  to  prevent  it  from  reacting

81
VII. Protection of Alcohols

A three-step process is required to achieve the

desired overall synthesis: (1) protect alcohol (2)
perform Grignard reaction, then (3) deprotect

Hello

82
VII. Protection of Alcohols

• One  such  protecting  group  is  trimethylsilyl  (TMS)  

Hello

• The  TMS  protection  step  requires  the  presence  of  a  base  to  
neutralize  the  HCl  byproduct

83
VII. Protection of Alcohols

• Evidence  suggests  that  substitution  at  the  Si  atom  occurs  by  an  SN2  
mechanism  
• Because  Si  is  much  larger  than  C,  it  is  more  open  to  backside  attack

Hello

84
VII. Protection of Alcohols

• The  TMS  group  can  later  be  removed  with  H3O+  or  F-­‐  

Hello

• TBAF  is  often  used  to  supply  fluoride  ions

85
VII. Protection of Alcohols

• The  overall  process  is  shown  below:

Hello

86
VII. Protection of Alcohols

Identify  the  reagents  that  you  would  use  to  accomplish  the  
following  synthetic  transformations.    

OH
Br
HO
a. Hello HO

HO
Br
HO
b. HO OH

87
 VII. Protection of Alcohols
Answers:    The  key  for  these  reactions  is  that  it  is  NOT  compatible  with  
alcohols  since  your  Grignard  reagents  become  expensive  and  face  bases  that  
simply  deprotonate  the  alcohol  to  make  the  alkoxide.    Therefore  you  must  
first  protect  the  alcohol  so  the  molecule  becomes  aprotic,  then  perform  the  
Grignard  reaction,  and  finally,  you  can  deprotect  the  alcohol.
OH
Hello 1. TMSCl, Et3N
Br 2. Mg
HO 3. acetone HO
a.
4. H2O
5. TBAF

TMSCl, Et3N TBAF

OH

Br 1. Mg
TMSO TMSO
2. O

3. H2O

88
 VII. Protection of Alcohols
Answers:    If  you  are  wondering  why  water  is  used  in  step  4,  it  is  
required  to  protonate  the  alkoxide  that  is  formed  after  the  Grignard  
reagent  is  added  to  the  carbonyl.
1. TMSCl, Et3N
2. Mg
3. O HO

HO
HelloMeO
Br
b. HO OH
4. H2O
5. TBAF

TMSCl, Et3N TBAF

Br HO
TMSO 1. Mg
O TMSO OTMS
2.
(0.5 equivalents)
MeO
3. H2O

0.5 equivalents of the methyl ester are required to guarentee that the Grignard addition happens twice.

89
VIII. Preparation of Phenols(Not on Tests or Quizzes)

• 2  million  tons  of  phenol  is  produced  industrially  yearly  

Hello

• Acetone  is  a  useful  byproduct  

• Phenol  is  a  precursor  in  many  chemical  syntheses  
– Pharmaceuticals  
– Polymers  
– Adhesives  
– Food  preservatives,  etc.
90
IX. Reactions of Alcohols: Substitution and Elimination

• 3˚  alcohols  area  converted  to  alkyl  halides  with  HX  (SN1  rxn)  

Hello

• For  1˚  or  2˚  alcohols,  the  reaction  occurs  via  SN2

91
IX. Reactions of Alcohols: Substitution and Elimination

• To  make  an  alkyl  chloride,  ZnCl2  must  be  used  with  HCl  

Hello

• The  Zinc  cation  is  required  to  make  the  –OH  a  better  leaving  group

92
IX. Reactions of Alcohols: Substitution and Elimination

• Recall  the  –OH  group  can  be  converted  into  a  good  leaving  group,  
such  as  a  tosyl  group  

Hello

• The  tosylate  can  then  undergo  

  SN2  substitution  to  obtain  an  
  alkyl  halide

93
IX. Reactions of Alcohols: Substitution and Elimination

1˚ and 2˚ alcohols can also be converted to alkyl halides

using SOCl2 or PBr3:

Hello

These conditions are milder than using a strong acid and

therefore more compatible with a variety of functional groups
IX. Reactions of Alcohols: Substitution and Elimination

• SOCl2  mechanism:

Hello

95
IX. Reactions of Alcohols: Substitution and Elimination

• PBr3  mechanism:  

Hello

96
IX. Reactions of Alcohols: Substitution and Elimination

• In  chapter  7,  we  saw  alcohols  undergo  elimination  in  acidic  

conditions:  

Hello

• 3˚  follow  an  SN1  mechanism  under  these  conditions:

97
IX. Reactions of Alcohols: Substitution and Elimination

• Recall  that  E1  elimination  generally  favors  the  more  substituted  

alkene  (thermodynamic  product).  

Hello

• The  less  substituted  alkene  could  only  be  favored  via  E2  
elimination  using  a  strong  bulky  base.

98
IX. Reactions of Alcohols: Substitution and Elimination

• If  the  alcohol  is  converted  into  a  better  leaving  group,  then  a  strong  
base  can  be  used  to  promote  E2  

Hello

• E2  reactions  generally  preferred  over  E1  reactions.    E2  pathway  not  

susceptible  to  rearrangements,  and  regioselectivity  can  be  
controlled  (Zaitsev  vs.  Hofmann)

99
IX. Reactions of Alcohols: Substitution and Elimination
Identify  the  reagents  that  can  be  used  to  accomplish  the  following  
transformation.    Hopefully  this  comes  as  a  review  to  you!

OH Br

a. d.
OH Br
Hello

OH Br

b. e.
HO Cl

c. f. OH Br
OH Cl

100
IX. Reactions of Alcohols: Substitution and Elimination
Answers:
OH Br

PBr3 SOCl2, py
a. c.
OH Cl

1. TsCl, py 1. TsCl, py
NaBr NaCl
OTs
Hello
OTs

For problems a and c, notice the inversion of stereochemistry. That means an SN2 reaction is
required. First the OH needs to be converted to a good leaving group, then the bromide ion
can displace that good leaving group to give inversion of stereochemistry.
OH Br

HBr
b.

There is nothing fancy occurring here. It is simply an SN1 reaction. The alcohol is protonated to
turning it into a better leaving group, which leaves. The bromide ion then attacks the highly
stabilized benzyl carbocation.
101
IX. Reactions of Alcohols: Substitution and Elimination
Answers:
These are all SN2 reactions which require an OH to become a better leaving group and result in
an inversion of stereochemistry. For problems d & e, you actually have 3 different ways to
accomplish this.
SOCl2, py
PBr3
d. e.
OH Br HCl
HO Cl
Hello ZnCl2

1. TsCl, py 1. TsCl, py
NaBr NaCl

OTs TsO

HBr

f. OH Br
PBr3

1. TsCl, py
NaBr

OTs
102
IX. Reactions of Alcohols: Substitution and Elimination
Predict  the  products  for  each  of  the  following  transformations

OH
a. conc. H2SO4
Hello heat

HO
b. 1. TsCl, py.
2. NaOEt

103
IX. Reactions of Alcohols: Substitution and Elimination
Answers:

OH conc. H2SO4
a.
+
heat

Hello minor major

The most thermodynamically stable alkene is expected to be the major product.

HO TsO EtO
1. TsCl, py. 2. NaOEt
b. +

minor major

For a leaving group on a secondary carbon, elimination occurs faster than substitution so the
alkene is the major product.

104
X. Reactions of Alcohols: Oxidation

• We  saw  how  alcohols  can  be  formed  by  the  reduction  of  a  carbonyl  

• The  reverse  process,  oxidation,  is  also  possible:

Hello

• The  word  oxidation  originally  meant  “add  oxygen”  or  add  oxygen  
bonds. 105
X. Reactions of Alcohols: Oxidation

• Oxidation  of  primary  alcohols  proceed  to  an  aldehyde,  and  then  to  
the  carboxylic  acid  

Hello

• Oxidation  of  secondary  alcohols  produces  a  ketone

• Oxidation  of  alcohols  typically  require  the  loss  of  alpha  

hydrogens. 106
X. Reactions of Alcohols: Oxidation

3˚ alcohols generally do not undergo oxidation because

they do not have any protons at the α position:

Hello

107
X. Reactions of Alcohols: Oxidation

• There  is  a  large  number  of  oxidizing  agents  that  can  be  used  to  
oxidize  an  alcohol  
• The  most  common  oxidizing  agent  is  chromic  acid;  it  is  formed  
from  either  CrO3  or  Na2Cr2O7  in  aqueous  acid:
Hello

Chromic  acid
is  also
called  the
Jones  Reagent

108
 X. Reactions of Alcohols: Oxidation

• Oxidation  of  the  alcohol  with  chromic  acid  involves  (1)  formation  of  
a  chromate  ester,  and  (2)  elimination  to  form  the  π  bond

Hello

• This  reaction  is  called  the  Jones  Oxidation

109
X. Reactions of Alcohols: Oxidation

• Chromic  acid  will  oxidize  a  1˚  alcohol  to  a  carboxylic  acid  

Hello

• PCC  (pyridinium  chlorochromate)  can  be  used  as  the  oxidant  to  
produce  an  aldehyde  

1˚  alcohol aldehyde

110
X. Reactions of Alcohols: Oxidation

• Regardless  of  the  oxidant  used,  either  chromic  acid  or  PCC  will  
convert  a  2˚  alcohol  to  a  ketone:

Hello

111
X. Reactions of Alcohols: Oxidation

• Chromium  reagents  are  toxic  and  horrible  for  the  environment.  

• Alternatives  have  been  developed,  two  of  them  are  covered  here:  

1. Swern  oxidation  –  dimethyl  sulfoxide  (DMSO)  and  oxalyl  

chloride  form  Hello
the  active  oxidant.  

active  
oxidant

112
X. Reactions of Alcohols: Oxidation

• The  chlorodimethyl  sulfonium  ion  (active  oxidant)  is  attacked  by  

the  alcohol,  and  Et3N  facilitates  elimination  to  form  the  π  bond  

Hello

• 2˚  alcohols  are  oxidized  to  ketones

113
X. Reactions of Alcohols: Oxidation

Like PCC, the Swern  oxidabon  converts 1˚  alcohols  to  

aldehydes

Hello

114
X. Reactions of Alcohols: Oxidation

• Chromium  reagents  are  toxic  and  horrible  for  the  environment.  

• Alternatives  have  been  developed,  two  of  them  are  covered  here:  

2. Dess-­‐Martin  periodane  oxidation  (DMP)  –  yields  analogous  

results  as  the  Hello
Swern  oxidation:

115
X. Reactions of Alcohols: Oxidation

• DMP  oxidation  is  believed  to  proceed  through  a  periodane  

intermediate:  

Hello

• DMP  oxidation  is  non-­‐acidic  and  doesn’t  require  high  temps,  but  
chromium  oxidations  do.

116
X. Reactions of Alcohols: Oxidation

Predict the product for the following reaction

Hello

117
X. Reactions of Alcohols: Oxidation

• Predict  the  product  for  the  following  reaction

carboxylic
2˚  alcohol ketone acid
aldehyde
Hello

1˚  alcohol carboxylic
acid

118
 X. Reactions of Alcohols: Oxidation
Predict  the  major  product  for  each  reaction

HO

Na2Cr2O7 1. DMSO, (COCl)2

a. OH d.
H2SO4, H2O 2. Et3N

Hello
HO

Na2Cr2O7 PCC
b. e. OH
H2SO4, H2O CH2Cl2

O
H
OH xs CrO3 DMP
c. f. H
H3O, acetone CH2Cl2
O
HO

119
 X. Reactions of Alcohols: Oxidation
Answers:      In  all  cases,  the  cromate  will  oxidize  the  alcohol,  or  aldehyde  as  far  as  
possible.    If  it  is  the  secondary  alcohol,  there  is  only  one  alpha  hydrogen  so  a  
ketone  is  produced.    If  it  is  a  primary  alcohol,  there  are  two  alpha  hydrogens  so  a  
carboxylic  acid  is  produced.    If  it  is  an  aldehyde,  there  is  one  alpha  hydrogen  so  it  
too  is  oxidized  to  the  carboxylic  acid.
Na2Cr2O7
a.
Hello
OH
H2SO4, H2O
O

HO O
OH
Na2Cr2O7
b.
H2SO4, H2O

O
H
OH xs CrO3 HO
c.
H3O, acetone OH
O
O
120
 X. Reactions of Alcohols: Oxidation
Answers:   HO
O
H

1. DMSO, (COCl)2
d.
2. Et3N

Even though there are two alpha hydrogens, the Swern Oxidation stops at the aldehyde and
Hello acid.
and will not oxidize it to the carboxylic

PCC O
e. OH
CH2Cl2

The oxidation stops at the ketone because it is a secondary alcohol; there is only one alpha
hydrogen.
O
O

DMP H
f. H
CH2Cl2
O
HO

H
Dess Martin-Periodinane (DMP) will oxidize a primary alcohol to an aldehyde. Any aldehydes
in the molecule are unaffected.
121
 X. Reactions of Alcohols: Oxidation
Galanthamine  is  a  natural  product  that  can  be  isolated  from  a  family  of  
flowering  plants.    It  has  also  been  used  in  the  early  treatment  of  Alzheimers  
disease.    As  part  of  this  synthesis,  compound  1  was  converted  into  
compound  2.    Propose  an  efficient  synthesis  for  this  transformation  (1  ⟶  2)

OMe Hello OMe

OMe

O H O H
O H
O O
OH
O O
H N
O Me
1 2 Galanthamine

122
X. Reactions of Alcohols: Oxidation
Answers:
OMe OMe
OMe

O H O H
1. BH3·THF O H
O 2. H2O2, NaOH
3. DMP, CH2Cl2 O
OH
O O

Hello O
H
Me
N

1
2 Galanthamine

1. BH3·THF DMP, CH2Cl2

2. H2O2, NaOH
or
OMe 1. DMSO, (COCl)2
2. Et3N Hydroboration is the first step since we need
O H
or anti-Markovnikov selectivity in forming the
O alcohol. The second step requires an oxidant
PCC, CH2Cl2
that will stop at the aldehyde. There are a few
O
different choices that you can use.
HO

123
XI. Biological Redox Reactions (Not on Tests or Quizzes)

• Nature  employs  reducing  and  oxidizing  agents  

• They  are  generally  complex  and  selective.  
• NADH  (below)  is  one  such  reducing  agent

Hello

124
XI. Biological Redox Reactions (Not on Tests or Quizzes)

• The  reactive  site  of  NADH  acts  as  a  hydride  delivery  agent  

Hello

• This  is  one  way  nature  

  converts  carbonyls  into    
  alcohols  

125
XI. Biological Redox Reactions (Not on Tests or Quizzes)

• NAD+  is  an  oxidant,  and  undergoes  the  reverse  process:  

Hello

• The  NADH  /  NAD+    

  interconversion  plays  a  
  key  role  in  metabolism

126
XI. Biological Redox Reactions (Not on Tests or Quizzes)

• Recall  that  tertiary  alcohols  do  not  undergo  oxidation,  because  

they  lack  an  alpha  proton  
• You  might  expect  phenol  to  be  similarly  unreactive  

Hello

• In  reality,  phenol  is  even  more  readily  oxidized  than  primary  or  
secondary  alcohols

127
XII. Oxidation of Phenol (Not on Tests or Quizzes)

• Phenol  oxidizes  to  form  benzoquinone,  which  in  turn  can  be  
reduced  to  hydroquinone  

Hello

• Quinones  interconvert  with  hydroquinones,  which  is  a  key  process  

in  cellular  respiration

128
XII. Oxidation of Phenol (Not on Tests or Quizzes)

Ubiquinones act to catalyze the conversion of

oxygen into water, and are found in all cells in
nature

Hello

129
XII. Oxidation of Phenol (Not on Tests or Quizzes)

Ubiquinone catalysis:

Hello

130
XIII. Synthesis Strategies

• Recall  that  reactions  fall  into  the  category  of  (1)  changing  the  
carbon  skeleton,  or  (2)  changing  a  functional  group  

• Some  reactions  covered  so  far:

Hello

131
XIII. Synthesis Strategies

Now we have reactions that interconvert 1˚ alcohols

with aldehydes, and 2˚ alcohols with ketones:

Hello

132
XIII. Synthesis Strategies

These 6 functional groups can be grouped by

oxidation state:

Hello

133
XIII. Synthesis Strategies

Hello

134
XIII. Synthesis Strategies

Recall the Grignard Reaction is a C-C bond forming

reaction:

Hello

135
XIII. Synthesis Strategies

• There  is  no  one  reaction  that  converts  an  aldehyde  into  a  ketone,  
but  with  a  Grignard  reaction  followed  by  oxidation,  it  can  be  
accomplished  in  two:

Hello

136
XIII. Synthesis Strategies
Propose  an  efficient  synthesis  for  the  following  transformation:
O

Hello

137
 XIII. Synthesis Strategies
Answers:    See  next  slide  for  the  answer
O

Strategies: Hello
OH O

or

138
XIII. Synthesis Strategies
Answers:  
1. H3O+
2. H2CrO4

Hello 1. Br2
2. xs NaNH2
3. H2O
4. H2SO4, H2O, HgSO4

Both methods will work, but arguably, the top approach is best since it requires far fewer
reagents. You also have more flexibility since several oxidizing agents can be used to
accomplish the second step (H2CrO4 is not the only answer)

In case you are confused about the bottom approach, Br2 followed by excess strong base will
give the alkyne. Water is added as the workup to neutralize any reagents left over. Step 4
converts the alkyne to the ketone.

139
 XIII. Synthesis Strategies
Propose  an  efficient  synthesis  for  each  of  the  following  
transformations:

a. d.
OH OH

Hello
O

b. OH e.
H

O
O
c. f.
H

140
 XIII. Synthesis Strategies
Answers:    With  synthesis  problems,  there  are  often  many  ways  to  make  the  
desired  product.    As  shown  by  the  two  different  approaches  for  part  a.    Also,  
many  different  reagents  may  be  available  to  you  for  a  given  step.

1. H2, Lindlar
2. BH3·THF 1. R2BH
3. H2O2, NaOH 2. H2O2, NaOH
a. 3. LiAl4
OH
Hello OH 4. H2O

1. H2, Lindlar 1. R2BH

2. H2O2, NaOH 1. LiAl4
1. BH3·THF 2. H2O
2. H2O2, NaOH

O
H

1. Br2
H2O, H2SO4 2. xs NaNH2
b. OH
∆ 3. H2O

TsCl, py

t-BuOK For this step, make sure you use DBU, DBN or t-
OTs BuOK. You do NOT want NaOMe since it will
displace the OTs though an SN2 reaction.
141
 XIII. Synthesis Strategies
Answers:    With  synthesis  problems,  there  are  often  many  ways  to  make  the  
desired  product.    As  shown  by  the  two  different  approaches  for  part  d.    Also,  
many  different  reagents  may  be  available  to  you  for  a  given  step.
1. BH3·THF O
2. H2O2, NaOH
c.
3. PCC, CH2Cl2 H

1. BH3·THF Hello
2. H2O2, NaOH PCC, CH2Cl2
OH
For step 2, make sure you use DBU, DBN or t-
BuOK. You do NOT want NaOMe since it will also
displace the OTs though an SN2 reaction forming
a minor byproduct

1. TsCl, py
1. H2O, H2SO4
d. 2. DBU, DBN, or t-BuOK
2. H2, Pt 3. H2, Pt
OH OH

H2, Pt
1. TsCl, py H2, Pt
H2O, H2SO4 2. t-BuOK

major or

142
XIII. Synthesis Strategies
Answers

O OH 1. H2O, H2SO4
1. LiAlH
e.
H 2. H2O or

1. TsCl, py
Hello 2. DBU, or t-BuOK

1. H2O, H2SO4
O OH
1. LiAlH or
f.
2. H2O
1. TsCl, py
2. NaOEt

143
XIII. Synthesis Strategies
Lithium  borohydride  (LiBH4)  is  a  useful  reducing  agent,  as  it  is  more  selective  than  
LiAlH4  but  less  selective  than  NaBH4.    For  example,  LiBH4  will  reduce  esters,  but  it  
will  not  reduce  amides  (carbonyl  adjacent  to  a  nitrogen).    This  strategy  is  regularly  
used  by  synthetic  organic  chemists.      
The  following  problem  is  a  portion  of  the  total  synthesis  of  (-­‐)-­‐croalbinecine,  a  
natural  product  with  cytotoxic  properties.    As  you  can  see,  compound  1  can  be  
converted  to  compound  Hello 3  in  two  steps.    Determine  the  identity  of  compounds  2  
and  3.

CO2Et
Ph
HO
1. Excess NaH,
1. Excess LiBH4 excess PhCH2Br, DMF
N 2 3
2. H2O 2. H2, Lindlar’s Catalyst
O

1
O

144
XIII. Synthesis Strategies
CO2Et
Ph
OH ONa

HO Ph
Ph
HO Excess NaH NaO
1. Excess LiBH4
N
O 2. H2O N N
O O
1
O 2

O O

Excess PhCH2Br

Answers
OBn

OBn Ph
BnO

BnO H2, Lindlar’s Catalyst N

N O
Ph
O

O
3 O

OBn = O

Bn = benzyl

145 145
XIII. Synthesis Strategies
Identify  the  reagents  required  for  the  following  transformations.

O O
a.

H
Hello

O O
b.
H

146
XIII. Synthesis Strategies
Answers
1. EtMgBr
O O
2. H2O
a.
3. PCC, CH2Cl2
H

1. EtMgBr
2. H2O PCC, CH2Cl2 Many other oxidizing agents can be used
Hello here such as Na2Cr2O7, DMP, or even the
Swern conditions 1. DMSO, (COCl)2, 2. Et3N
OH

O 1. MeMgBr O
b. 2. H2O
H 3. PCC, CH2Cl2

1. MeMgBr
2. H2O OH PCC, CH2Cl2

147
XIII. Synthesis Strategies
Propose  an  efficient  synthesis  for  the  following  transformation:

Hello

148
 XIII. Synthesis Strategies
Answers

3
1. R2BH
1 5
2. H2O2, NaOH 4
1
4 2 Bad Approah O
3 3. MeMgBr O
2 4. H2O 3
1 5 + 1 5
5. PCC, CH2Cl2 3
2 4 4
4 2
1

1. R2BH
Hello PCC, CH2Cl2 2
3 O

2. H2O2, NaOH
1. NaNH2 will give mixture of products
2. MeI
3 1 3
1 4 H 1. MeMgBr 4 5
2 2. H2O 2
4
O OH 1
3
2

149
 XIII. Synthesis Strategies
Propose  an  efficient  synthesis  for  each  of  the  following  
transformations:
OH

a. d.

O
Hello O

O
O
e.
b.

OH
O O OH

c. H f.

150
 XIII. Synthesis Strategies
Answers:    As  always  there  are  multiple  ways  to  solve  this  problem.    There  are  also  
multiple  reagents  that  can  be  used  to  accomplish  the  same  oxidation.    I  tend  to  use  
PCC  all  the  time  because  it  is  easy  to  remember,  but  don't  forget  about  the  other  
oxidizing  agents  in  case  you  come  across  one  on  an  exam  or  ACS  test

1. BH3·THF
3
a.
1
Hello
2 4
2. H2O2, NaOH 1
3. PCC, CH2Cl2 2
3
4
5

4. MeMgBr
5. H2O O
6. PCC, CH2Cl2 PCC
CH2Cl2
1. Br2 1. BH3·THF
2. xs NaNH2 2. H2O2, NaOH
3. H2O

1 3 1 3 1 3
2 OH PCC 2 O 1. MeMgBr 2 4 OH
4 CH2Cl2 4 2. H2O
5

1. R2BH
2. H2O2, NaOH

151
XIII. Synthesis Strategies
Answers 1 3
O
7
b. 2 5
1 2 4 6

O OH O
+ EtMgBr
H
Hello
Retrosynthetic Analysis

I +

1. NaNH2
2. propyl iodide
3. R2BH O
4. H2ONaOH
5. EtMgBr
6. H2O Na2Cr2O7,
7. Na2Cr2O7, H2SO4, H2O H2SO4, H2O
1. NaNH2
2. propyl iodide

O OH
1. R2BH 1. EtMgBr
2. H2O, NaOH 2. H2O
H
152
 XIII. Synthesis Strategies
Answers
O O
1 1. EtMgBr 1
2 3 2. H2O 2 3 4 5
H
c.
3. DMSO, (COCl)2 As  always  you  don’t  have  to  use  the  Swern  
4. Et3N
oxidation  here.  PCC,  DMP  and  Na2Cr2O7  
1. EtMgBr will  all  work.
1. DMSO, (COCl)
2. H2O Hello
2. Et N 3
2

OH

racemic

153
Answers
XIII. Synthesis Strategies O
+ MeMgBr
O OH H

Retrosynthetic Analysis
OH
OH

1. TsCl, py
OH 2. t-BuOK
3. BH3·THF 1
1 PCC OH
2 3 4 4. H2O2, NaOH 2 3 4 5
d.
5. DMP, DCM DCM
6. MeMgBr O
7. H2O
8. PCC, DSM
1. TsCl, py 1. MeMgBr
2. t-BuOK 2. H2O

1. BH3·THF OH DMP O
2. H2O2, NaOH DCM
H

154 154
XIII. Synthesis Strategies
Answers
1. R2BH O
2. H2O2, NaOH 4
3
3. MeMgBr
3
e. 2 4. H2O 2
1 5. Na2Cr2O7, 1
H2SO4, H2O
Hello
Na2Cr2O7,
1. R2BH H2SO4, H2O
2. H2O2, NaOH

OH
O 1. MeMgBr
2. H2O
H

155
XIII. Synthesis Strategies
Answers

OH
OH 1. PCC, DCM
2
2. MeMgBr 1 3
f. 1 2 3 3. H2O
Hello 4

PCC,
DCM

1. MeMgBr
O 2. H2O

156